The purpose of this project is to find genes that impair cortical function and, in doing so, increase the risk for developing schizophrenia. The method to be used is the affected sibling pair paradigm. Abnormalities of cortical function appear to be core features of chronic schizophrenia. Cortical function of patients and their siblings will be quantified using functional MRI, MR Spectroscopy and neuropsychological testing. Results using these methods will be combined with genetic data to look for genes that affect brain function and increase susceptibility to schizophrenia. Carefully diagnosed probands will recruited from our existing in patient population of persons with chronic schizophrenia. Other probands are recruited through the media and the National Alliance for the Mentally Ill. Diagnosis of probands is established from previous psychiatric records and a structured diagnostic interview. Siblings and control subjects likewise are evaluated with a structured interview. All subjects give a blood sample for genetic analysis. Evaluation of cortical function is done using functional MRI and neuropsychological testing. These procedures have been chosen because it is already known that persons with schizophrenia demonstrate some abnormality compared to normal controls. We have recently shown that subsets of the siblings show one or more abnormal traits on these tests, thus suggesting that they are phenotypically similar to their ill sibling even though they do not evidence (at the time of testing) the full blown syndrome. This study and the method of genetic analysis is unique in that it does not use diagnosis as the identifying variable. Instead, we look at intermediate biological variables. We anticipate that this will increase the statistical power to find schizophrenia genes. Our initial results have been very promising in this regard. A specific gene on chromosome 22, called COMT, is important in regulating prefrontal dopamine metabolism and cognitive processes subserved by the prefrontal cortex. These cognitive processes, generically refered to as working memory and executive function, are impaired in patients with schizophrenia. We have recently shown that a variant of the COMT gene impairs working memory and executive function and, in doing so, slightly increases risk for developing schizophrenia.